Roberto J. Guiloff

Widespread loss of neuronal populations in the spinal ventral horn in sporadic motor neuron disease. A morphometric study

The cytopathology and loss of neurons was studied in 7670 neurons from the ventral horn of the third lumbar segment of the spinal cord of six sporadic motor neuron disease (MND) patients compared with 7568 neurons in seven age matched control subjects. A modified Tomlinson et al. [Tomlinson BE, Irving D, Rebeiz JJ. Total numbers of limb motor neurones in the human lumbosacral cord and an analysis of the accuracy of various sampling procedures. J Neurol Sci 1973;20:313-27] sampling procedure was used for neuronal counts. The ventral horn was divided in quadrants. Neuronal populations were also classified by the maximum cell diameter through the nucleolus. There was widespread loss of neurons in all quadrants of the ventral horn in MND. Size distribution histograms showed similar neuron loss across all populations of neurons. The dorsomedial quadrant contains almost exclusively interneurons and the ventrolateral quadrant mostly motor neurons. The cytopathology of neurons in the dorsomedial quadrant and of large motorneurons in the ventrolateral quadrant MND was similar. In the dorsomedial quadrant, neuron loss (56.7%) was similar to the loss of large motor neurons in the ventrolateral quadrant (64.4%). The loss of presumed motor neurons and interneurons increased with increased disease duration. There was no evidence that loss of presumed interneurons occurred prior, or subsequent, to loss of motor neurons. We conclude that, in sporadic MND, all neuronal populations in the ventral horn are affected and that interneurons are involved to a similar extent and in parallel with motor neurons, as reported in the G86R transgenic mouse model of familial MND. The increasing evidence of loss of neurons other than motor neurons in MND suggests the need for revising the concept of selective motor neuron vulnerability.

Dysarthria in amyotrophic lateral sclerosis: A review

Dysarthria is a motor disorder of speech characterized by abnormalities of the articulation and intelligibility of speech. Phonation and the rate of facial movements may also be affected. Understanding the nature and course of dysarthria in amyotrophic lateral sclerosis (ALS) is important because loss of communication prevents patients from participating in many activities, may lead to social isolation, and reduces the quality of life. The goal of management of dysarthria in ALS patients is to optimize communication effectiveness for as long as possible. The information about dysarthria in ALS is dispersed in physiological, pathological, speech therapy, otorhinolaringological and neurological publications. This review summarizes the current state of knowledge on the clinical features, differential diagnosis, pathophysiology, investigations and management of dysarthria in ALS patients. There is a need to compare the different methods used to assess dysarthria and for controlled clinical trials to assess therapeutic strategies.

Ubiquitin immunoreactivity in presumed spinal interneurones in motor neurone disease

Previous studies have demonstrated the presence of ubiquitin‐immunoreactivity (Ub‐IR) as inclusions and skeins in motor neurones of both the familial and sporadic forms of motor neurone disease (MND). There is evidence that interneurones also degenerate in MND, but Ub‐IR in ventral horn spinal interneurones has not been studied previously. Here, Ub‐IR was investigated in 1445 presumed interneurones and 1086 presumed motor neurones counted in three random 20‐µm sections of the ventral horn of the third lumbar segment of the spinal cord of each of seven controls and seven patients with MND. The ventral horn was divided into four quadrants; the dorsomedial quadrant contains almost exclusively interneurones and the ventrolateral quadrant largely motor neurones. The neurones were also classified by morphological and size criteria into presumed interneurones (< 25 µm) and presumed motor neurones (≥ 25 µm). Ub‐IR was classified as inclusions, skeins and dispersed cytoplasmic and nuclear staining. Ub‐IR inclusions or skeins were not observed in the controls but 6.6% of neurones (motor neurones and interneurones) showed the presence of dispersed cytoplasm staining and nuclear staining. The incidence of Ub‐IR cytoplasmic and nuclear staining was significantly greater in both motor neurones and interneurones of MND patients than controls. Ub‐IR was less frequent in MND cases in which a great loss of neurones was observed. Ub‐IR was significantly more frequent in motor neurones than interneurones, both in patients and controls. Ub‐IR inclusions and skeins were only observed in motor neurones from MND patients. Ub‐IR inclusions were not observed in presumed spinal interneurones, while skeins were only seen in three out of 565 of these cells (two of them in the dorsomedial quadrant) in two out of seven patients. Thus, although presumed spinal interneurones occasionally revealed Ub‐IR features similar to motor neurones, the rare staining of Ub‐IR skeins and the lack of Ub‐IR inclusions in interneurones in MND suggests that these neurones only occasionally form ubiquitin–protein conjugates. Neuronal size, rather than type, may be important in determining whether ubiquitin–protein conjugates form in the ventral horn neurones in MND.

Interneuronal survival and calbindin-D28k expression following motoneuron degeneration.

Degeneration of both motoneurons and interneurons has been previously observed in amyotrophic lateral sclerosis. It is unclear whether interneuronal loss is due to an intrinsic neuronal defect or if it occurs secondary to loss of their target motoneurons. We have examined the target dependence of interneurons, their survival and alterations in the expression of the calcium binding protein, calbindin-D28k (CB), in the ventral horn of the rat lumbar cord after extensive motoneuron degeneration was induced by unilateral rhizotomy of spinal nerves L2-L6 at postnatal day 3 (P3). Counts of Nissl-stained cells at P21 revealed no significant interneuronal death despite loss of 80% of their target motoneurons. At P6, some motoneurons transiently expressed CB on the operated side compared to the control side. Since most of these cells are destined to die, this transiently increased CB expression may represent an abortive attempt by the axotomised motoneurons to buffer the neurotoxic consequences of high intracellular calcium. In contrast, there was a time-dependent decrease in CB expression in ventral horn interneurons, with only 35% of putative Renshaw cells expressing CB by P21. These results indicate that neonatal interneurons are capable of surviving the loss of their motoneuron targets, but alter their phenotype as indicated by functional alterations in calcium-binding proteins.

Amyotrophic lateral sclerosis and ocular flutter

Abstract A previously unreported association of amyotrophic lateral sclerosis and ocular flutter is presented. It is hypothesized that initial loss of brainstem inhibitory interneurons resulted in disinhibition of burst interneurons and that the ocular flutter subsequently disappeared as burst interneurons also became affected by the disease process. The association adds clinical evidence of involvement of brainstem interneurons to other evidence of involvement of neurons other than motor neurons in the disease process.

Nineteen-year follow-up of Waldenström's-associated neuropathy and Bing–Neel syndrome

We describe the follow‐up of a patient with Waldenströms macroglobulinemia who developed mild predominantly sensory peripheral neuropathy, Bing–Neel syndrome, and, after 17 years, acute mononeuropathy multiplex associated with increasing paraprotein levels. Nerve biopsy demonstrated deposition of IgM in the endoneurium and perineurium. Magnetic resonance imaging showed extension of the cerebral white‐matter abnormality. We suggest that the pathogenetic mechanism of the mononeuropathy multiplex may include direct IgM deposition. Late peripheral nerve complications appeared to be related to the paraprotein level.

Limitations of inferences from observational databases in amyotrophic lateral sclerosis: all that glitters is not gold.

Data from three observational databases have suggested that survival in patients with ALS who take riluzole is far greater than that reported in randomized controlled studies. This editorial discusses why therapeutic efficacy cannot be inferred from observational databases. Data in these databases cannot control for biases in treatment assignment or for differences in intensity of follow-up or supportive care. The retrospective riluzole data, as presented so far, have not demonstrated comparability between the treated and untreated groups across all known prognostic factors, including vital capacity at the start of the observation period. Furthermore, the similarity of untreated patients to historical cohorts likely reflects adverse selection. Optimization of analysis in retrospective studies may be accomplished by allowing full access to data to all interested parties.

SCA3 Presenting as an Isolated Axonal Polyneuropathy

OBJECTIVES To highlight an unexpected clinical presentation and to review the associated polyneuropathy phenotypes of SCA3. DESIGN Clinical follow-up. SETTING Neurological referral center. PATIENT Middle-aged man with no family history for SCA3. RESULTS Presentation with an isolated axonal, distal, symmetric, sensorimotor polyneuropathy for 6 years before developing a cerebellar syndrome prompting genetic testing for SCA3. CONCLUSION SCA3 can present with an isolated axonal, distal, symmetric, sensorimotor polyneuropathy.

Familial limb pain and migraine: 8-year follow-up of four generations.

Background Migraine limb pain may be under-recognized in adults and children. There is little information about familial forms of this disorder. Objectives To describe the clinical and inheritance patterns of familial migraine limb pain over four generations and to review the evidence for limb pain as a manifestation of migraine. Methods Prospective clinical and pedigree analysis with an 8-year follow-up of 27 family members. Results Eight members of the family had benign recurrent limb pain associated with headache in a dominant inheritance pattern. Limb pain occurred before, during or after the headache, with probable or definite migraine with aura, migraine without aura and lower-half headache. The limb pain fulfilled the International Headache Society criteria for aura in six patients and also occurred without headache in three. Four members of the family had recurrent abdominal pain and/or motion sickness in childhood. Conclusions This is the first report of dominant familial limb pain temporally associated with migraine headache, starting in adulthood or starting in childhood and continuing into adulthood. A search for a genetic marker is indicated. Limb pain should be included as a childhood periodic syndrome linked to migraine and recognized as part of the migraine spectrum in adults.

Spinal cord infarction with ipsilateral segmental neuropathic pain and flaccid paralysis. A functional role for human afferent ventral root small sensory fibres

This paper illustrates the cases of two patients with an acute onset of right brachial neuropathic pain, flaccid paralysis and contralateral thermal and thermal pain hypoesthesia, without posterior column impairment nor pyramidal signs below the segmental lesion. MRI showed right sided spinal cord infarction, in the anterior spinal artery territory between C1 and C5 in one patient and between C3 and C7 in the other. Contact Heat Evoked Potentials and Quantitative Thermal Sensory testing are consistent with contralateral, but not ipsilateral, spinothalamic tract involvement. Electromyographic results established ipsilateral segmental denervation and somatosensory evoked responses were consistent with dorsal column sparing. Unilateral anterior cervical spinal cord infarction may present with acute ipsilateral segmental neuropathic pain, lower motor neurone-type weakness, contralateral thermoanalgesia and no pyramidal signs. The ipsilateral pain provides novel evidence that in some instances, ventral roots can play a role in nociception in humans. The infarcted territory may result from occlusion of a sulcal commissural artery or a number of more proximal vessels (including a single or duplicated anterior spinal artery, vertebral arteries or feeding radicular arteries).